JPH0513132B2 - - Google Patents
Info
- Publication number
- JPH0513132B2 JPH0513132B2 JP60260868A JP26086885A JPH0513132B2 JP H0513132 B2 JPH0513132 B2 JP H0513132B2 JP 60260868 A JP60260868 A JP 60260868A JP 26086885 A JP26086885 A JP 26086885A JP H0513132 B2 JPH0513132 B2 JP H0513132B2
- Authority
- JP
- Japan
- Prior art keywords
- water
- drug
- release
- elution
- tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229940079593 drug Drugs 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 30
- 229920003169 water-soluble polymer Polymers 0.000 claims description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 239000007939 sustained release tablet Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims description 3
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 239000000017 hydrogel Substances 0.000 claims description 2
- 238000000748 compression moulding Methods 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 24
- 238000010828 elution Methods 0.000 description 21
- 238000004090 dissolution Methods 0.000 description 16
- 239000000499 gel Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
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- 230000000694 effects Effects 0.000 description 5
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- -1 oxyfebutazone Chemical compound 0.000 description 5
- 238000013268 sustained release Methods 0.000 description 5
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- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 4
- 229920002125 Sokalan® Polymers 0.000 description 4
- 239000002702 enteric coating Substances 0.000 description 4
- 238000009505 enteric coating Methods 0.000 description 4
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- 229960000581 salicylamide Drugs 0.000 description 4
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- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
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- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 229940124630 bronchodilator Drugs 0.000 description 2
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- 238000007906 compression Methods 0.000 description 2
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- 238000009472 formulation Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 229960000278 theophylline Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 1
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 1
- GJHKWLSRHNWTAN-UHFFFAOYSA-N 1-ethoxy-4-(4-pentylcyclohexyl)benzene Chemical compound C1CC(CCCCC)CCC1C1=CC=C(OCC)C=C1 GJHKWLSRHNWTAN-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- AKUVRZKNLXYTJX-UHFFFAOYSA-N 3-benzylazetidine Chemical compound C=1C=CC=CC=1CC1CNC1 AKUVRZKNLXYTJX-UHFFFAOYSA-N 0.000 description 1
- XZRKEDHJXXLVSK-UHFFFAOYSA-N 6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide;6-phenylpteridine-2,4,7-triamine Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O.NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 XZRKEDHJXXLVSK-UHFFFAOYSA-N 0.000 description 1
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- RHAXSHUQNIEUEY-UHFFFAOYSA-N Epirizole Chemical compound COC1=CC(C)=NN1C1=NC(C)=CC(OC)=N1 RHAXSHUQNIEUEY-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- RGCVKNLCSQQDEP-UHFFFAOYSA-N Perphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 RGCVKNLCSQQDEP-UHFFFAOYSA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
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- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- YWXYYJSYQOXTPL-JGWLITMVSA-N [(3r,3ar,6s,6as)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] nitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-JGWLITMVSA-N 0.000 description 1
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- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
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- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 1
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
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- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
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- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
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- 239000000935 antidepressant agent Substances 0.000 description 1
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- 239000002220 antihypertensive agent Substances 0.000 description 1
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- 239000002246 antineoplastic agent Substances 0.000 description 1
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- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
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- IVHBBMHQKZBJEU-UHFFFAOYSA-N cinchocaine hydrochloride Chemical compound [Cl-].C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCC[NH+](CC)CC)=C21 IVHBBMHQKZBJEU-UHFFFAOYSA-N 0.000 description 1
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- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
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- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
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- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
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- 229940030606 diuretics Drugs 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
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- AUAHHJJRFHRVPV-BZDVOYDHSA-N ethambutol dihydrochloride Chemical compound [Cl-].[Cl-].CC[C@@H](CO)[NH2+]CC[NH2+][C@@H](CC)CO AUAHHJJRFHRVPV-BZDVOYDHSA-N 0.000 description 1
- 229960001618 ethambutol hydrochloride Drugs 0.000 description 1
- 229960000514 ethenzamide Drugs 0.000 description 1
- SBNKFTQSBPKMBZ-UHFFFAOYSA-N ethenzamide Chemical compound CCOC1=CC=CC=C1C(N)=O SBNKFTQSBPKMBZ-UHFFFAOYSA-N 0.000 description 1
- HAPOVYFOVVWLRS-UHFFFAOYSA-N ethosuximide Chemical compound CCC1(C)CC(=O)NC1=O HAPOVYFOVVWLRS-UHFFFAOYSA-N 0.000 description 1
- 229960002767 ethosuximide Drugs 0.000 description 1
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- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
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- 239000003193 general anesthetic agent Substances 0.000 description 1
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- 229960005384 hydralazine hydrochloride Drugs 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960004708 noscapine Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229960000762 perphenazine Drugs 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
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- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
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- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
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- 239000011782 vitamin Substances 0.000 description 1
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- 235000013343 vitamin Nutrition 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Description
（産業上の利用分野）
本発明は経口投与型の徐放性錠剤の改良された
製造方法に関する。従来経口投与型の徐放性製剤
としては、薬物自体を加工したものを除き、薬物
の放出制御には、半透膜を利用する浸透圧による
ものとマトリツクス中の薬物の拡散によるものと
に大別されるが、本発明は、後者に分類される。
すなわち、水溶性高分子が水と接触したとき形成
される高分子ゲル中を薬物が拡散溶出することに
より、除放化が達成されているタイプのものであ
る。
（従来の技術と問題点）
このようなタイプの薬物の放出制御について
は、すでに各種の特許が存在する。例えばヒドロ
キシプロピルメチルセルロース、カルボキシメチ
ルセルロースを用いるものとして米国特許第
3065143号、ヒドロキシプロピルメチルセルロー
スの水分およびエチルセルロースの添加による放
出制御として米国特許第3870790号、ヒドロキシ
プロピルメチルセルロースの変性によるもとして
米国特許第4226849号、ヒドロキシプロピルメチ
ルセルロースの粘度による放出制御として米国特
許第4369172号、米国特許第4389393号がある。
徐放性製剤は本来血中または作用部位における
薬物濃度を長時間治療濃度範囲に維持し、薬効発
現時間を延長させることが目的であるため、製剤
からの薬物放出は０次速度、すなわち一定速度で
あることが好ましい。
従来の方法により得られる錠剤は長時間にわた
つて薬物を放出させるという観点からは、満足で
きるものであるが、０次速度の放出に関しては必
ずしも、満足するものではない。何故ならこの型
の徐放性製剤は溶出が進むにつれ、有効溶出面積
の減少を伴う結果、溶出速度は徐々に遅延すると
いう問題がある。
一方、特開昭60−185728号公報にはヒドロキシ
プロピルメチルセルロース、ヒドロキシプロピル
セルロースおよびカルボキシビニル重合体を含む
徐放性医薬担体組成物が記載されていて、このカ
ルボキシビニル重合体の効果により小腸中のアル
カリ条件下で０次放出を示すと説明されている。
しかし、本発明者らが検討したところでは、こ
のカルボキシビニル重合体をヒトの平均的な胃液
および腸液に相当するPH１〜２およびPH６〜７の
水中に加えると、いずれも粘性の液にはなるが、
PHが高いほど粘性が高くなるという性質があるた
め、カルビキシビニル重合体を含む徐放性錠剤は
PH１〜２の液に対するよりもPH６〜７の液におけ
る方が崩壊が遅く、ヒトの消化過程を想定した崩
壊試験、例えば日本薬局方の腸溶性製剤の崩壊試
験法にしたがつて試験液に第１液を用いて120分
間、引き続いて第２液を用いて試験を行うと、０
次放出を示さないことが認められた。
これはカルボキシビニル重合体がこれらの試験
液に接触すると、その部分で高分子ゲルが形成さ
れるが、第２液を用いたときは第１液を用いたと
きよりも粘性の大きいゲルが形成され、そのため
ゲルの侵食が遅く崩壊しにくくなるための考えら
れる。
一般に、ヒドロキシプロピルメチルセルロース
などのヒドロゲル形成能のある水溶性高分子の単
一のものを徐放性医薬担体として含む徐放性製剤
では、これらの放出動態は放出量と放出開始後の
時間の平方根が比例関係にある。したがつて初期
の溶出速度を適切な範囲に調節すると後期の溶出
速度が小さくなり目的とする時間内に薬物が完全
に溶出せず、残りは消化器管内を通過してしまう
おそれがある。
一方目的とする時間内に100％溶出を完了させ
ようとすると初期の溶出速度が速すぎ、血中また
は作用部位ので薬物濃度が上昇し、その結果副作
用の発現が増加したり、溶出後期に血中または作
用部位での薬物濃度が低下し、治療効果が減少す
ることが考えられる。
本発明者らはPHに依存して溶解または崩壊する
特性をもつた腸溶性コーテイング基材に着目し、
体温付近の温度で水と接触すると水を吸収、膨潤
してゲル化層を形成する、いわゆるヒドロゲル形
成能のある水溶性高分子に腸溶性コーテイング基
材としてヒドロキシプロピルメチルセルロースア
セテートサクシネート（以下、HPMCASとす
る）を添加すれば溶出特性が容易に制御でき溶出
遅延が防止されることを見出し本発明を完成する
ことができた。
（発明の構成）
本発明は薬物とヒドロゲル形成能のある水溶性
高分子とHPMCASとを主体とする組成物を、圧
縮成型することを特徴とする経口投与型徐放性錠
剤の製造方法を提供するものである。
本発明における薬物は消化管より吸収されるも
のであれば特に限定されない。
代表的な有効薬物としては、インドメタシン、
ジクロフエナツク、イブプロフエン、フエニルブ
タゾン、オキシフエブタゾン、メピリゾール、ア
スピリン、エテンザミド、アミノピリン、フエナ
セチン等の消炎、鎮痛薬、イソニアジド、塩酸エ
タンブトール、抗生物質等の抗結核薬、硝酸イソ
ソルビド、ニトログリセリン、ニフエジピン等の
冠血管拡張薬、塩酸ヒドララジン、メチルドー
パ、フロセミド、スピノロラクトン、硫酸グアネ
チジン、レセルピン等の抗高血圧薬、塩酸クロル
プロマジン、ハロベリドール、ペルフエナジン、
ジアゼパム等の向精神薬、マレイン酸クロルフエ
ニラミン、塩酸ジフエンヒドラミン等の抗ヒスタ
ミン薬、硝酸チアミン、アスコルビン酸、ニコチ
ン酸アミド等のビタミン類、アロプリノール、コ
ルヒチン、プロベネジド等の痛風薬、アモバルビ
タール、プロムワレリル尿素、抱水クロラール等
の催眠鎮静薬、フルオロウラシル、シクロホスフ
アミド、チオテバ等の抗悪性腫瘍薬、フエニルプ
ロパノールアミン、エフエドリン類等の抗うつ血
薬、アセトヘキサミド、インシユリン、トルブタ
ミド等の糖尿病薬、ヒドロクロロチアジド、トリ
アムテレン等の利尿薬、アミノフイリン、テオフ
イリン等の気管支拡張薬、リン酸コデイン、ノス
カピン、デキストロメトルフアン等の鎮咳薬、硫
酸キニジン、ジキトキシン、プロカインアミド等
の抗不整脈薬、アミノ安息香酸エチル、リドカイ
ン、塩酸ジブカイン等の表面麻酔薬、フエニトイ
ン、エトスクシミド、プリミドン等の抗てんかん
薬、ヒドロコルチゾン、プレドニゾロン、トリア
ムシノロン、ベメタゾン等の合成副腎皮質ステロ
イド類があげられる。
また、剤型はその組成が均一であるならば錠剤
以外に顆粒剤または顆粒剤を充てんしたカプセル
剤とすることができる。
ヒドロゲル形成能のある水溶性高分子としては
ゲル形成能の高いセルロース系高分子が適当で、
たとえばヒドロキシプロピルメチルセルロース
（HPMC）、メチルセルロース（MC）、ヒドロキ
シエチルメチルセルロース（HEMC）、ヒドロキ
シプロピルセルロース（HPC）、カルボキシメチ
ルセルロース（CMC）又はその塩および部分架
橋物があり、特にヒドロキシプロピルメチルセル
ロースが適している。その他の天然水溶性高分子
としては、プルラン、アルギン酸ソーダ等があげ
られる。これらはいずれも水溶性であるが、溶解
する以前に水に接すると膨潤し、粘性の高いゲル
を形成する。従つて、薬物はこのゲル中を拡散し
たのち放出されることになる。
腸溶性コーテイング基材としてのHPMCAS
は、高分子として可塑性が高く、またセルロース
系であるために相手側に水溶性高分子としてヒド
ロキシプロピルメチルセルロースを選択した場
合、親和性が高く得られた錠剤の硬度が高くな
り、またゲル層の溶解速度を高度に制御できる。
また、この粒度は日本薬局方48号ふるいを通過
するものが90％以上さらに好ましくは、その上
100号ふるいを通過するものが50％以上のものが
用いられる。
本発明における水溶性高分子の粘度は、セルロ
ースエーテルとしてたとえば、20℃における２重
量％水溶液の粘度が３〜100000センチポイズ好ま
しくは15〜10000センチポイズのものが用いられ、
主薬の含量、水に対する溶解性、徐放性時間など
から適するグレードが選ばれる。
その他の添加剤としては、必要に応じた量の賦
形剤、縮合剤、崩壊剤、滑沢剤、着香料、着色
剤、保存剤、界面活性剤等を加えることができ
る。
錠剤の製法としては、たとえば薬物と水溶性高
分子とHPMCASに賦形剤、滑沢剤を加えて混合
し打錠するいわゆる直接打錠法によるか、または
薬物と水溶性高分子を主体としてこれに水を加え
て、練合し製粒するなどの湿式造粒法により打錠
末を調整し、これに残りの錠剤成分を加えて混合
し、打錠する方法が採用できる。この際、水溶性
高分子とHPMCASの組成比は、90：10〜50：50
の範囲内で用いられ、HPMCASがこれより少な
い場合は、その効果は十分に現われず、また多い
場合は良好なゲル層の形成が困難となる。さら
に、水溶性高分子とHPMCASを含めた量と残り
の錠剤組成との比は主薬の含量及びその溶解性と
ゲル層での拡散速度により決まるが、好ましくは
15：85〜99：１の範囲にある。
（発明の効果）
本発明の方法による錠剤は、錠剤が水と接触し
たとき錠剤表面に軟いゲル層が形成され、薬物は
そのゲル層を通して徐々に溶出することになるた
め、溶出の遅延はなく、ほどんど０次に近い溶出
特性を示し、生体内（invivo）試験を行なうと、
対照よりも良い持続効果が得られる。これは配合
された腸溶性基材としてのHPMCASがPHの低い
領域では、特に作用しないで、溶出後期の腸内の
PHの高い領域で崩壊剤的機能を持つためであり、
それによつて溶出速度が大幅に改善されるので生
物学的利用率（バイオアベイラビリテイー）の向
上が期待される。
実施例 １
気管支拡張薬、テオフイリンを、表−１に示す
錠剤組成とし、10mm型を用い打錠圧100Kg／cm2で
打錠した。
(Industrial Field of Application) The present invention relates to an improved method for producing sustained release tablets for oral administration. Conventionally, for orally administered sustained-release preparations, excluding those in which the drug itself is processed, drug release can be controlled mainly by osmotic pressure using a semipermeable membrane and by diffusion of the drug in a matrix. However, the present invention falls into the latter category.
That is, this type of drug achieves sustained release by diffusion and elution of the drug through a polymer gel that is formed when a water-soluble polymer comes into contact with water. (Prior Art and Problems) Various patents already exist regarding this type of drug release control. For example, US Patent No.
No. 3,065,143, US Pat. No. 3,870,790 for controlling the release of hydroxypropyl methylcellulose by adding moisture and ethyl cellulose, US Pat. No. 4,226,849 for modifying hydroxypropyl methylcellulose, and US Pat. , U.S. Pat. No. 4,389,393. The original purpose of sustained-release preparations is to maintain the drug concentration in the blood or at the site of action within a therapeutic range for a long period of time and to prolong the onset of drug efficacy, so the drug is released from the preparation at a zero-order rate, that is, at a constant rate. It is preferable that Although tablets obtained by conventional methods are satisfactory in terms of releasing drugs over a long period of time, they are not necessarily satisfactory in terms of zero-order rate release. This is because this type of sustained-release preparation has a problem in that as dissolution progresses, the effective elution area decreases, and as a result, the dissolution rate gradually slows down. On the other hand, JP-A-60-185728 describes a sustained-release pharmaceutical carrier composition containing hydroxypropylmethylcellulose, hydroxypropylcellulose, and a carboxyvinyl polymer. It is described as exhibiting zero-order release under alkaline conditions. However, according to the inventors' studies, when this carboxyvinyl polymer is added to water with a pH of 1 to 2 and a pH of 6 to 7, which correspond to average human gastric and intestinal fluids, both become viscous liquids. but,
Since the higher the pH, the higher the viscosity, sustained-release tablets containing carboxyvinyl polymers
Disintegration is slower in a liquid with a pH of 6 to 7 than in a liquid with a pH of 1 to 2, and a disintegration test that simulates the human digestive process, such as the Japanese Pharmacopoeia's disintegration test method for enteric-coated preparations, is performed in a test liquid. When the test is carried out using one solution for 120 minutes, followed by the second solution, the result is 0.
It was observed that no subsequent release was observed. This is because when the carboxyvinyl polymer comes into contact with these test solutions, a polymer gel is formed in that area, but when the second solution is used, a gel with higher viscosity is formed than when the first solution is used. This is thought to be the reason why the gel erodes slowly and becomes difficult to collapse. Generally, for sustained release formulations containing a single hydrogel-forming water-soluble polymer such as hydroxypropyl methylcellulose as the sustained release pharmaceutical carrier, these release kinetics are determined by the square root of the amount released and the time after the onset of release. are in a proportional relationship. Therefore, if the initial dissolution rate is adjusted to an appropriate range, the dissolution rate in the latter phase will be small, and there is a risk that the drug will not be completely eluted within the intended time and the remainder will pass through the gastrointestinal tract. On the other hand, if you try to complete 100% dissolution within the desired time, the initial dissolution rate will be too fast and the drug concentration will increase in the blood or at the site of action, resulting in an increase in the occurrence of side effects or in the late stage of elution. It is conceivable that the drug concentration in or at the site of action is reduced, reducing therapeutic efficacy. The present inventors focused on an enteric coating base material that has the property of dissolving or disintegrating depending on pH,
Hydroxypropyl methyl cellulose acetate succinate (hereinafter referred to as HPMCAS) is used as an enteric coating base material for water-soluble polymers with so-called hydrogel-forming ability, which absorb water and swell to form a gelled layer when they come into contact with water at temperatures around body temperature. The inventors have found that the elution characteristics can be easily controlled and elution delay can be prevented by adding the following compounds: (Structure of the Invention) The present invention provides a method for producing an orally administered sustained-release tablet, which comprises compressing and molding a composition mainly consisting of a drug, a water-soluble polymer capable of forming a hydrogel, and HPMCAS. It is something to do. The drug in the present invention is not particularly limited as long as it is absorbed from the gastrointestinal tract. Typical effective drugs include indomethacin,
Anti-inflammatory and analgesic drugs such as diclofenac, ibuprofen, phenylbutazone, oxyfebutazone, mepirizole, aspirin, ethenzamide, aminopyrine, and phenacetin; antituberculous drugs such as isoniazid, ethambutol hydrochloride, and antibiotics; and drugs such as isosorbide nitrate, nitroglycerin, and nifedipine. Vasodilators, hydralazine hydrochloride, methyldopa, furosemide, spinololactone, guanethidine sulfate, antihypertensive drugs such as reserpine, chlorpromazine hydrochloride, haloberidol, perphenazine,
Psychotropic drugs such as diazepam, antihistamines such as chlorpheniramine maleate and diphenhydramine hydrochloride, vitamins such as thiamine nitrate, ascorbic acid and nicotinamide, gout medicines such as allopurinol, colchicine and probenezide, ammo Hypnotic and sedative drugs such as barbital, promvalerylurea, and chloral hydrate; antineoplastic drugs such as fluorouracil, cyclophosphamide, and thioteba; antidepressants such as phenylpropanolamine and ephedrin; acetohexamide, insulin, tolbutamide, etc. diabetic drugs, diuretics such as hydrochlorothiazide and triamterene, bronchodilators such as aminophylline and theophylline, antitussive drugs such as codeine phosphate, noscapine, and dextromethorphan, antiarrhythmic drugs such as quinidine sulfate, dioquitoxin, and procainamide; Examples include surface anesthetics such as ethyl aminobenzoate, lidocaine, and dibucaine hydrochloride, antiepileptic drugs such as phenytoin, ethosuximide, and primidone, and synthetic corticosteroids such as hydrocortisone, prednisolone, triamcinolone, and bemethasone. In addition, the dosage form may be granules or capsules filled with granules in addition to tablets, as long as the composition is uniform. Cellulose-based polymers with high gel-forming ability are suitable as water-soluble polymers with hydrogel-forming ability.
Examples include hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), hydroxyethylmethylcellulose (HEMC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC) or their salts and partially crosslinked products, with hydroxypropylmethylcellulose being particularly suitable. . Other natural water-soluble polymers include pullulan, sodium alginate, and the like. All of these are water-soluble, but when they come in contact with water before they dissolve, they swell and form a highly viscous gel. Therefore, the drug will be released after diffusing in this gel. HPMCAS as enteric coating substrate
has high plasticity as a polymer and is cellulose-based, so if hydroxypropyl methylcellulose is selected as a water-soluble polymer for the other party, the hardness of the resulting tablet will be high due to its high affinity, and the gel layer will be hard. Dissolution rate can be highly controlled. In addition, the particle size is preferably 90% or more that passes through a Japanese Pharmacopoeia No. 48 sieve.
The material that passes through a No. 100 sieve of 50% or more is used. The viscosity of the water-soluble polymer used in the present invention is, for example, a cellulose ether having a viscosity of 3 to 100,000 centipoise, preferably 15 to 10,000 centipoise in a 2% by weight aqueous solution at 20°C.
The appropriate grade is selected based on the content of the active ingredient, solubility in water, sustained release time, etc. As other additives, excipients, condensing agents, disintegrants, lubricants, flavoring agents, coloring agents, preservatives, surfactants, etc. can be added in amounts as required. For example, tablets can be manufactured by the so-called direct tableting method, in which the drug, water-soluble polymer, and HPMCAS are mixed with excipients and lubricants, and then tableted, or by the direct compression method, in which the drug and water-soluble polymer are mainly mixed. A method can be adopted in which a tablet powder is prepared by a wet granulation method such as adding water, kneading, and granulating, and adding the remaining tablet components to this, mixing, and tableting. At this time, the composition ratio of water-soluble polymer and HPMCAS is 90:10 to 50:50.
If the amount of HPMCAS is less than this, the effect will not be sufficiently exhibited, and if it is more than this, it will be difficult to form a good gel layer. Furthermore, the ratio of the amount including the water-soluble polymer and HPMCAS to the remaining tablet composition is determined by the content of the active ingredient, its solubility, and the diffusion rate in the gel layer, but is preferably
It is in the range of 15:85 to 99:1. (Effects of the Invention) In the tablet produced by the method of the present invention, a soft gel layer is formed on the tablet surface when the tablet comes into contact with water, and the drug gradually dissolves through the gel layer, so that the dissolution is delayed. It exhibits elution characteristics that are almost zero-order, and when in vivo tests are conducted,
A better lasting effect than the control is obtained. This is because HPMCAS as an enteric-coated base material does not particularly act in areas with low pH, and is
This is because it has a disintegrant function in the high pH range,
This greatly improves the elution rate and is expected to improve bioavailability. Example 1 A bronchodilator, theophylline, was prepared into a tablet having the composition shown in Table 1, and was compressed into tablets using a 10 mm mold at a compression pressure of 100 Kg/cm 2 .
【表】
なお、上記HPMC（60SH−50）、HPMC（60SH
−400）、HPMCASはいずれも信越化学工業(株)製
であり、それらの粒度はそれぞれ100号ふるい通
過率で98.5％％，97.0％，98.3％，200号ふるいで
73.6％，78.3％，86.5％であつた。
得られた錠剤は、モンサント錠剤硬度計にて硬
度を測定し、日本薬局方（10局）規定の溶出試験
液を用いパドル法（パドル回転数100rpm）にて、
腸溶性製剤の崩壊試験法に準じて溶出試験を実施
した。硬度はいずれも20Kg以上であり十分な強度
を示した。この場合得られた錠剤、各１錠につい
て日本薬局方第１液900mlを、溶出液として２時
間溶出試験し、その後ただちに溶出液を日本薬局
方第２液900mlに交換して溶出試験を経続した。
溶出試験結果は第１図に示すとおりであり、比
較例Ａと本発明Ｃでは８時間の溶出率は同等であ
るが初期の２時間の溶出率はそれぞれ39％と21％
であり、初期の溶出を抑えた場合にも速やかな溶
出が認められた。また溶出曲線は、本発明の組成
では、時間と溶出率の関係がほぼ直線的で０次に
近い溶出特性を示したのに対し、比較例では、初
期の溶出速度は速いが時間と共に遅くなる傾向が
みられた。また本発明の組成から腸溶性コーテイ
ング基材を除いた処方では本発明のＣに比べ著し
く、溶出速度が遅くまた、その速度は徐々に減少
した。
実施例 ２
薬物として、マレイン酸クロルフエニラミンを
用い表−２に示す錠剤組成で実施例１に従い打錠
した。
硬度は、いずれも20Kg以上であつた。[Table] In addition, the above HPMC (60SH-50), HPMC (60SH
-400) and HPMCAS are both manufactured by Shin-Etsu Chemical Co., Ltd., and their particle sizes are 98.5%, 97.0%, 98.3%, and 98.3%, respectively, through a No. 100 sieve.
The percentages were 73.6%, 78.3%, and 86.5%. The hardness of the obtained tablets was measured using a Monsanto tablet hardness meter, and the hardness was measured using the paddle method (paddle rotation speed: 100 rpm) using a dissolution test solution specified by the Japanese Pharmacopoeia (10 Bureaus).
A dissolution test was conducted according to the disintegration test method for enteric-coated preparations. All had hardnesses of 20 kg or more, indicating sufficient strength. In this case, each tablet obtained was subjected to a dissolution test using 900 ml of Japanese Pharmacopoeia Liquid 1 as an eluent for 2 hours, and then the eluate was immediately replaced with 900 ml of Japanese Pharmacopoeia Liquid 2 and the dissolution test was continued. did. The dissolution test results are shown in Figure 1, and the dissolution rates at 8 hours are the same in Comparative Example A and Invention C, but the dissolution rates at the initial 2 hours are 39% and 21%, respectively.
, and rapid elution was observed even when the initial elution was suppressed. In addition, the elution curve of the composition of the present invention showed a nearly linear relationship between time and elution rate, and an elution characteristic close to zero order, whereas in the comparative example, the initial elution rate was fast but slowed down with time. A trend was observed. Furthermore, in the formulation of the present invention in which the enteric coating base material was removed, the dissolution rate was significantly slower than that of C of the present invention, and the rate gradually decreased. Example 2 Tablets were compressed according to Example 1 using chlorpheniramine maleate as the drug and having the tablet composition shown in Table 2. The hardness was 20 kg or more in all cases.
【表】【table】
【表】
実施例１に従い、錠剤各１錠を用い溶出液とし
てそれぞれ第１液500mlと第２液500mlを用い２時
間で液交換を行なつた。
溶出試験の結果は第２図に示すとおりであり、
比較例Ｄと本発明Ｆ、比較例Ｅと本発明Ｇ，Ｈで
はそれぞれ、溶出の遅延防止効果が現われてい
る。また本発明ＨではHPMCの高粘度品種との
組み合せで、初期の溶出も抑制されより０次に近
い溶出特性が得られている。
実施例 ３
薬物として、サリチルアミドを用い表−３に示
す錠剤組成で実施例１に従い打錠した。[Table] According to Example 1, one tablet was used and 500 ml of the first liquid and 500 ml of the second liquid were used as the eluent, and the liquid was exchanged over a period of 2 hours. The results of the dissolution test are shown in Figure 2.
In Comparative Example D and Invention F, and in Comparative Example E and Inventions G and H, the elution delay prevention effect appears. In addition, in the present invention H, in combination with a high viscosity type of HPMC, initial elution is also suppressed and elution characteristics closer to zero order are obtained. Example 3 Tablets were compressed according to Example 1 with the tablet composition shown in Table 3 using salicylamide as the drug.
【表】【table】
【表】
得られた錠剤を人体に投与し、生体内試験を行
なつた。吸収放出の指標となるサリチルアミドの
尿中排せつ物について１時間ごとに尿試料を集め
分析した。その結果を第３図に示した。
この実験結果はサリチルアミドが特定吸収部位
をもたず、吸収から***までの時間が短いため
に、比較例Ｉおよび本発明Ｊの消火管内でのサリ
チルアミド放出状態を良く現わし、Ｉでは徐々に
放出速度が低下しているが、Ｊではおおよそ一定
速度で放出されていることを明らかに示してい
る。
実施例 ４
薬物としてα−メチルドパを用い、表−４に示
す錠剤組成で実施例１に従い打錠した。[Table] The obtained tablets were administered to humans and in vivo tests were conducted. Urine samples were collected every hour and analyzed for urinary excretion of salicylamide, which is an indicator of absorption and release. The results are shown in Figure 3. This experimental result clearly shows the release state of salicylamide in the fire extinguishing pipes of Comparative Example I and Invention J because salicylamide does not have a specific absorption site and the time from absorption to excretion is short; It clearly shows that the release rate is decreasing in J, but the release rate is approximately constant in J. Example 4 Using α-methyldopa as the drug, tablets were compressed according to Example 1 with the tablet composition shown in Table 4.
【表】
これら組成を湿式で造粒し、打錠に適当な粒度
に調粒し、残りの錠剤組成を加えて混合し、８
mm、6Rの臼と杵を用いてロータリー式の打錠機
で、打錠圧1.5トンにて打錠した。
得られた錠剤は、いずれも硬度20Kg以上で、十
分な強度を有していた。
溶出試験結果を第４図に示した。比較例Ｋと本
発明Ｍでは、８時間の溶出率は同一であるが、初
期の２時間の溶出率はそれぞれ28％と14％であ
り、本発明の効果が十分に現われほぼ０次に近い
溶出特性を示した。
実施例 ５
表−５に示す錠剤組成としたほかは実施例１と
同様にして打錠し、得られた各１錠について溶出
試験を行い、その結果を第５図に示した。[Table] Wet-granulate these compositions, adjust the particle size to an appropriate particle size for tableting, add the remaining tablet composition and mix.
The tablets were compressed using a rotary tablet press using a 6R mm mortar and punch at a compression pressure of 1.5 tons. All of the obtained tablets had a hardness of 20 kg or more and had sufficient strength. The results of the elution test are shown in Figure 4. Comparative Example K and Invention M have the same dissolution rate at 8 hours, but the dissolution rates at the initial 2 hours are 28% and 14%, respectively, indicating that the effect of the present invention is fully evident and is close to zero order. The elution characteristics were shown. Example 5 Tablets were compressed in the same manner as in Example 1 except that the tablet composition shown in Table 5 was used, and each tablet obtained was subjected to a dissolution test, and the results are shown in FIG.
【表】【table】
【表】
図に示すように、初期２時間の溶出率は比較例
０で28％であつたのに対し本発明Ｎでは31％とほ
ぼ同等であるが、８時間の溶出率は本発明Ｎで約
100％に対し比較例０では63％であつた。
このように溶出曲線は本発明Ｎでは０次に近い
溶出特性を示したのに対し、比較例０では初期の
溶出速度が本発明Ｎとほぼ同じであつた後、時間
と共に遅くなる傾向が見られた。[Table] As shown in the figure, the dissolution rate for the initial 2 hours was 28% for Comparative Example 0, whereas it was 31% for Invention N, which is almost the same, but the dissolution rate for 8 hours was 28% for Comparative Example 0. approx.
Compared to 100%, it was 63% in Comparative Example 0. In this way, the elution curve of Invention N showed a nearly zero-order elution characteristic, whereas in Comparative Example 0, the initial elution rate was almost the same as Invention N, and then it tended to slow down with time. It was done.
第１〜第５図は薬物の溶出試験結果を時間と溶
出率で示す曲線図である。
FIGS. 1 to 5 are curve diagrams showing drug dissolution test results in terms of time and dissolution rate.
Claims (1)
ロキシプロピルメチルセルロースアセテートサク
シネートと薬物とを主体とする組成物を、圧縮成
型することを特徴とする経口投与型徐放性錠剤の
製造方法。 ２ 前記水溶性高分子とヒドロキシプロピルメチ
ルセルロースアセテートサクシネートとが、90：
10〜50：50の比である特許請求の範囲第１項記載
の経口投与型徐放性錠剤の製造方法。 ３ 前記水溶性高分子が、ヒドロキシプロピルメ
チルセルロース、メチルセルロース、ヒドロキシ
プロピルセルロースおよびヒドロキシエチルメチ
ルセルロースである特許請求の範囲第１項記載の
経口投与型徐放性錠剤の製造方法。[Scope of Claims] 1. An orally administered sustained release tablet characterized by compression molding a composition mainly consisting of a water-soluble polymer capable of forming a hydrogel, hydroxypropyl methylcellulose acetate succinate, and a drug. Production method. 2 The water-soluble polymer and hydroxypropyl methyl cellulose acetate succinate are 90:
The method for producing an orally administered sustained release tablet according to claim 1, wherein the ratio is 10 to 50:50. 3. The method for producing an orally administered sustained-release tablet according to claim 1, wherein the water-soluble polymer is hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, and hydroxyethylmethylcellulose.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26086885A JPS62120315A (en) | 1985-11-20 | 1985-11-20 | Production of sustained release tablet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26086885A JPS62120315A (en) | 1985-11-20 | 1985-11-20 | Production of sustained release tablet |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62120315A JPS62120315A (en) | 1987-06-01 |
| JPH0513132B2 true JPH0513132B2 (en) | 1993-02-19 |
Family
ID=17353866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP26086885A Granted JPS62120315A (en) | 1985-11-20 | 1985-11-20 | Production of sustained release tablet |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62120315A (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA881301B (en) * | 1987-02-27 | 1989-10-25 | Lilly Co Eli | Sustained release matrix formulations |
| DE3810343A1 (en) * | 1988-03-26 | 1989-10-05 | Basf Ag | Process for the production of solid pharmaceutical sustained release forms |
| US5174998A (en) * | 1988-11-30 | 1992-12-29 | Nisshin Flour Milling Co., Ltd. | Sustained release compositions using as matrix hemicellulose extracted from wheat bran |
| WO1994003159A1 (en) * | 1992-07-31 | 1994-02-17 | Daratech Pty. Ltd. | Controlled release implants |
| US5695781A (en) * | 1995-03-01 | 1997-12-09 | Hallmark Pharmaceuticals, Inc. | Sustained release formulation containing three different types of polymers |
| DK0996429T3 (en) * | 1997-10-27 | 2003-05-26 | Merck Patent Gmbh | Solid solutions and solid dispersions in water heavily soluble drugs |
| US6419954B1 (en) * | 2000-05-19 | 2002-07-16 | Yamanouchi Pharmaceutical Co., Ltd. | Tablets and methods for modified release of hydrophilic and other active agents |
| EP1530458A1 (en) * | 2002-08-14 | 2005-05-18 | Ranbaxy Laboratories, Ltd. | Extended release matrix tablets |
| JP4837895B2 (en) * | 2003-03-17 | 2011-12-14 | 武田薬品工業株式会社 | Controlled release composition |
| MX2009002235A (en) * | 2006-08-30 | 2009-03-13 | Jagotec Ag | Controlled release solid oral dosage formulations comprising nisoldipine. |
| CA2669324C (en) * | 2006-11-13 | 2012-06-19 | Kyorin Pharmaceutical Co., Ltd. | Method for preparing sustained release tablet |
| JP5699339B2 (en) | 2010-02-12 | 2015-04-08 | 日産化学工業株式会社 | Sustained release formulation |
| US20120039999A1 (en) * | 2010-08-11 | 2012-02-16 | Ashish Chatterji | Pharmaceutical compositions of metabotropic glutamate 5 receptor (mglu5) antagonists |
| US20120251588A1 (en) * | 2011-03-30 | 2012-10-04 | Miyuki Fukasawa | Coating Composition, Solid Preparation Coated Therewith, and Method for Preparing Solid Preparation |
| US11382912B2 (en) | 2017-11-16 | 2022-07-12 | Nippon Shinyaku Co., Ltd. | Controlled-release preparation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55118414A (en) * | 1979-03-05 | 1980-09-11 | Teijin Ltd | Prolonged release drug and its preparation |
| JPS55118413A (en) * | 1979-03-05 | 1980-09-11 | Teijin Ltd | Prolonged release drug and its preparation |
| JPS60185728A (en) * | 1983-12-01 | 1985-09-21 | ハンス ロウエイ | Slow release medicine carrier |
-
1985
- 1985-11-20 JP JP26086885A patent/JPS62120315A/en active Granted
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55118414A (en) * | 1979-03-05 | 1980-09-11 | Teijin Ltd | Prolonged release drug and its preparation |
| JPS55118413A (en) * | 1979-03-05 | 1980-09-11 | Teijin Ltd | Prolonged release drug and its preparation |
| JPS60185728A (en) * | 1983-12-01 | 1985-09-21 | ハンス ロウエイ | Slow release medicine carrier |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62120315A (en) | 1987-06-01 |
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